Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice
- Dayne A Beccano-Kelly
- Sarah A Paschall
- Naila Kuhlmann
- Chelsie A Kadgien
- Jesse Fox
- Jaskaran Khinda
- Emma Mitchell
- Heather Melrose
- Austen J Milnerwood
- Eurac Research, Italy
- University of Oxford, United Kingdom
- University of British Columbia, Canada
- Mayo Clinic, United States
- McGill University, Canada
Figures
Figure 1 with 1 supplement
Increased exploratory behavior in young GKI mice declines with age.
(A) Animal body weight over time. There was no main effect of genotype upon mouse weight, but there was a significant interaction between weight and age (see text and Figure 1—figure supplement 1). …
Figure 1—figure supplement 1
Weights of WT, GKI and GKI homozygous animals are similar until advanced ages.
Animal body weight over time. There was no main effect of genotype upon mouse weight, but there was a significant interaction between weight and age (2-way ANOVA, genotype p=0.17, interaction …
Figure 2 with 7 supplements
Increased glutamate transmission onto young GKI striatal projection neurons declines with age.
(A) Whole-cell voltage-clamp (WC VC) recording in striatal medium-sized spiny projection neurons (SPNs) of the dorsolateral striatum of acutely prepared brain slices. Recording electrodes targeted …
Figure 2—figure supplement 1
There are no genotype-dependent alterations to SPN intrinsic membrane properties.
Whole-cell recording of medium-sized spiny striatal projection neurons (SPNs) in membrane test mode and analysis of intrinsic membrane properties. While significant age-dependent changes in membrane …
Figure 2—figure supplement 2
GKI SPN sEPSC frequency is similarly increased in 1 and 3 month slices, and similar to WT in 12 and 18 month slices.
Whole-cell recording in dorsolateral striatal SPNs and analysis of sEPSCs recorded at −70 mV. Higher sEPSC frequencies (as reflected by decreased inter-event intervals) underlie significant main …
Figure 2—figure supplement 3
Spontaneous EPSCs recorded in dorsolateral striatum in the coronal slice preparation are TTX insensitive.
(A.i) Example traces of spontaneous EPSCs (sEPSCs) in whole-cell voltage-clamp (WCVC) recordings in striatal projection neurons (SPN) of the dorsolateral striatum, prior to, and in the presence of, …
Figure 2—figure supplement 4
There are no differences in the number of postsynaptic specializations, or presynaptic excitatory nerve terminal markers in the striatum of young or aged GKI mice.
(A) Representative bright-field images of Golgi-impregnated medium-sized spiny projection neurons (SPNs) of the dorsolateral striatum from WT and GKI mice aged 1–3 months (i), with inserts showing a …
Figure 2—figure supplement 5
Paired-pulse facilitation profiles in the striatum of aged GKI mice are similar and GKI mutant PPRs are insensitive to dopamine agonism and antagonism.
Whole-cell patch clamp recording and eEPSC paired-pulse experiments. (i) There were no significant differences in glutamatergic paired-pulse ratio at > 12 months, similarly to the 1–3 month age …
Figure 2—figure supplement 6
Spontaneous EPSCs recorded in GKI dorsolateral striatum SNPs are remoxipride insensitive.
Spontaneous EPSCs (sEPSCs) were recorded prior to, and in the presence of, remoxipride (Remox; 10 uM). (A) There was no significant effect of remoxipride upon mean sEPSC amplitude (paired t-test …
Figure 2—figure supplement 7
There were no differences in GKI sEPSC frequency between D1- and D2-dopamine receptor expressing SPNs, and no consistent effect of quinpirole upon eEPSC peak or PPR in either cell type.
Whole-cell patch clamp recording in D1 vs. D2-type SPNs in GKI slices. (A) There were no differences in sEPSC mean event frequency in either cell type at young (1–3 m) or old (>12 m) age points. (B) …
Figure 3 with 1 supplement
Increased nigrostriatal dopamine transmission in young GKI slices is lost with age, whereas early increases in dopamine extracellular lifetime are maintained in old GKI slices, and matched by age-related increases in WT slices.
Fast-scan cyclic voltammetry (FSCV) was conducted in the dorsolateral striatum of acute slices prepared from WT and GKI mice. (A) Dopamine release and reuptake transients were evoked by single or …
Figure 3—figure supplement 1
Early alterations in GKI dopamine release are not associated with reductions in nigrostriatal dopamine markers and persist despite genotype-dependent increases in DAT protein levels by western blot.
(A). Staining for presynaptic dopamine markers DAT and tyrosine hydroxylase (TH; i) showed highly specific enrichment in the striatum; however, there were no age or genotype differences (ii). …
Additional files
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Transparent reporting form
- https://doi.org/10.7554/eLife.28377.014
